The present invention is related to novel intermediates which are useful in the preparation of certain piperidine derivatives which are useful as antihistamines, antiallergy agents and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981, U.S. Pat. No. 4,285,958, Apr. 25, 1981 and U.S. Pat. No. 4,550,116, Oct. 29, 1985].
These antihistaminic piperidine derivatives can be described by the following formula: 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen;
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is xe2x80x94COOH or xe2x80x94COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof,
with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
The present invention provides novel intermediates useful for the preparation of certain antihistaminic piperidine derivatives of formula (I) 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is xe2x80x94COOH or xe2x80x94COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof,
with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
These novel intermediates are described by the following formulas: 
wherein
A is a hydrogen or hydroxy; and
R5 is H, xe2x80x94CH2OD wherein D is hydrogen, acetate or benzoate, xe2x80x94CHO, Br, Cl, I, CN, xe2x80x94COOH, xe2x80x94COOalkyl or xe2x80x94CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy. 
wherein
A is a hydrogen or hydroxy; and
R5 is H, Br, Cl, I, CN, xe2x80x94COOH, xe2x80x94COOalkyl or xe2x80x94CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy. 
wherein
A is a hydrogen or hydroxy; and
R5 is H, Br, Cl, I, CN, xe2x80x94COOH, xe2x80x94COOalkyl or xe2x80x94CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy. 
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R5 is H, CH2OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl, I, CN, xe2x80x94COOH or xe2x80x94CONR6R7 wherein R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy. 
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R5 is H, Br, Cl, I, CN, xe2x80x94COOH, xe2x80x94COOalkyl or xe2x80x94CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy. 
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy;
R5 is H, Br, Cl, I, CN, xe2x80x94COOH, xe2x80x94COOalkyl or xe2x80x94CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy. 
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5; and
A is a hydrogen or hydroxy. 
wherein A is a hydrogen or hydroxy. 
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R5 is H, CH2OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl, I, CN, xe2x80x94COOH, xe2x80x94COOalkyl or xe2x80x94CONR6R7 wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy; and
individual optical isomers thereof. 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R5 is H, Br, Cl, I, CN or xe2x80x94CONR6R7 wherein R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy;
A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
In addition, the present invention provides novel processes for preparing the antihistaminic piperidine derivatives of formula 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is xe2x80x94COOH or xe2x80x94COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a cumene compound of the formula 
wherein A is as defined above with a xcfx89-halo compound of the formula 
wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a xcfx89-halo cumylketone compound;
(b) reacting the xcfx89-halo cumylketone compound with a suitable halogenating agent to give a xcfx89-halo-halocumylketone compound;
(c) reacting the xcfx89-halo-halocumylketone compound compound with a suitable cyanating agent to-give a xcfx89-halo-cyanocumylketone compound;
(d) reacting the xcfx89-halo-cyanocumylketone compound with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid imidate compound;
(e) reacting the xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid imidate compound with water to give a xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound;
(f) reacting the xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound with a piperidine compound of the formula 
wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94;
(g) optionally hydrolyzing the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94;
(h) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with a suitable reducing agent to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94; and
(i) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the appropriate xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94 or a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94; and
(j) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94with an appropriate deprotecting reagent,
with the proviso that each of the hydroxy groups present in the compounds described in steps a-i are optionally protected or unprotected.
In addition, the present invention provides novel processes for preparing the antihistaminic piperidine derivatives of formula 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is xe2x80x94COOH or xe2x80x94COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a xcfx89-halo-halocumylketone compound with carbon dioxide under electrochemical reduction conditions to give a xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic compound;
(b) reacting the xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic compound compound with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound;
(c) reacting the xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound with a piperidine compound of the formula
wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and Wxe2x95x90xe2x80x94C(xe2x95x90O)xe2x80x94;
d) optionally hydrolyzing the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is 
COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOR and W is xe2x80x94C(xe2x95x90O)xe2x80x94;
(e) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with a suitable reducing agent to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94; and
(f) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the appropriate xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94 or a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94; and
(g) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94with an appropriate deprotecting reagent,
with the proviso that each of the hydroxy groups present in the compounds described in steps a-f are optionally protected or unprotected.
In addition, the present invention provides novel processes for preparing the antihistaminic piperidine derivatives of formula 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer 3;
m is an integer 0 or 1;
R3 is xe2x80x94COOH or xe2x80x94COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a cumyl compound of the formula 
wherein A is as defined above with an appropriate cyclopropyl compound of the structure 
wherein B is halo or hydroxy, in the presence of a suitable Lewis acid to produce a cyclopropyl cumylketone compound;
(b) reacting the cyclopropyl cumylketone compound with a suitable halogenating agent to give a cyclopropyl halocumylketone compound;
(c) reacting the cyclopropyl halocumylketone compound with carbon dioxide under electrochemical reduction conditions to give a cyclopropylketo-xcex1,xcex1-dimethylphenylacetic acid compound;
(d) reacting the cyclopropylketo-xcex1,xcex1-dimethylphenylacetic with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound;
(e) reacting the xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound with a piperidine compound of the formula 
wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and Wxe2x95x90xe2x80x94(xe2x95x90O)xe2x80x94;
(f) optionally hydrolyzing the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (1) wherein R3 is COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (1) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94;
(g) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with a suitable reducing agent to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94; and
(h) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the appropriate xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94 or a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94; and
(i) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94with an appropriate deprotecting reagent,
with the proviso that each of the hydroxy groups present in the compounds described in steps a-h are optionally protected or unprotected.
Another embodiment of the present invention involves a process for preparing the piperidine derivatives of formula 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is xe2x80x94COOH or xe2x80x94COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a xcex1,xcex1-dimethylphenylacetic acid amide compound of the formula 
wherein A is as defined above and R6 and R7 are each independently H, C1-C6alkyl, C1-C6alkoxy or R6 and R7 taken together with the nitrogen atom for a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7 cannot both be represented by C1-C6alkoxy with a xcfx89-halo compound of the formula 
wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid amide compound;
(b) reacting the xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid amide compound with a piperidine compound of the formula 
wherein R1 and R2 are as defined above in the presence of a suitable non-nucleophilic base to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (XI)
wherein R5 is xe2x80x94CONR6R7 wherein R6 and R7 are as defined above;
(c) optionally hydrolyzing the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (XI) wherein R5 is xe2x80x94CONR6R7 wherein R6 and R7 are as defined above to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94;
(d) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with a suitable reducing agent to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94; and
(e) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the appropriate xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94or a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94; and
(f) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94with an appropriate deprotecting reagent,
with the proviso that each of the hydroxy groups present in the compounds described in steps a-e are optionally protected or unprotected.
Another embodiment of the present invention involves a process for preparing the piperidine derivatives of formula 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is xe2x80x94COOH or xe2x80x94COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a toluene compound of the formula 
wherein A is as defined above with a xcfx89-halo compound of the formula 
wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a xcfx89-halo-tolylketone compound;
(b) reacting the xcfx89-halo-tolylketone compound with a suitable base to give a cyclopropyl-tolylketone compound;
(c) reacting the cyclopropyl-tolylketone compound with a suitable halogenating agent to give a cyclopropyl-halotolylketone compound;
(d) reacting the cyclopropyl-halotolylketone compound with a suitable cyanating agent to give a cyclopropyl cyanotolylketone compound;
(e) reacting the cyclopropyl cyanotolylketone compound with a suitable methylating agent to give a cyclopropyl cyanocumylketone compound;
(f) reacting the cyclopropyl cyanocumylketone compound with a suitable base to give a cyclopropylketo-xcex1,xcex1-dimethylphenylacetic acid amide;
(g) reacting the cyclopropylketo-xcex1,xcex1-dimethylphenylacetic acid amide with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound;
(h) reacting the xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound with a piperidine compound of the formula 
wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative;
(i) optionally hydrolyzing the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94;
(j) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with a suitable reducing agent to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94; and
(k) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the appropriate xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (II) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94or a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (II) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94, and
(l) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (II) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (II) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94with an appropriate deprotecting reagent,
with the proviso that each of the hydroxy groups present in the compounds described in steps a-k are optionally protected or unprotected.
Another embodiment of the present invention involves a process for preparing the piperidine derivatives of formula 
wherein
W represents xe2x80x94C(xe2x95x90O)xe2x80x94or xe2x80x94CH(OH)xe2x80x94;
R1 represents hydrogen or hydroxy;
R2 represents hydrogen; or
R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R3 is xe2x80x94COOH or xe2x80x94COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a phenylacetic acid ester compound of the formula 
wherein A is as defined above with a xcfx89-halo compound of the formula 
wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-phenylacetic acid ester compound;
(b) reacting the xcfx89xe2x80x2-halo-xcex1xe2x80x2-keto-phenylacetic acid ester compound with a suitable methylating agent in the presence of a suitable base to give a cyclopropylketo-xcex1,xcex1-dimethylphenylacetic acid ester;
(c) purifying the cyclopropylketo-xcex1,xcex1-dimethylphenylacetic acid ester by distillation and/or recrystallization;
(d) reacting the cyclopropylketo-xcex1,xcex1-dimethylphenylacetic acid ester with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give xcex1xe2x80x2-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound;
(e) reacting the xcfx89-halo-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenylacetic acid ester compound with a piperidine compound of the formula 
wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94;
(f) optionally hydrolyzing the xcfx89-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94;
(g) optionally reacting the xcfx89-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with a suitable reducing agent to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94; and
(h) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the appropriate xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl ad W is xe2x80x94CH(OH)xe2x80x94or a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94; and
(i) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94with an appropriate deprotecting reagent,
with the proviso that each of the hydroxy groups present in the compounds described in steps a-h are optionally protected or unprotected.
(g) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2--keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with a suitable reducing agent to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94; and
(h) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the appropriate xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94or a xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94; and
(i) optionally reacting the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89-piperidine-xcex1xe2x80x2-keto-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94C(xe2x95x90O)xe2x80x94, the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl derivative of formula (I) wherein R3 is xe2x80x94COOH and W is xe2x80x94CH(OH)xe2x80x94or the xcfx89xe2x80x2-piperidine-xcex1xe2x80x2-hydroxy-xcex1,xcex1-dimethylphenyl of formula (I) wherein R3 is xe2x80x94COOalkyl and W is xe2x80x94CH(OH)xe2x80x94with an appropriate deprotecting reagent,
with the proviso that each of the hydroxy groups present in the compounds described in steps a-h are optionally protected or unprotected.
As used herein, the term xe2x80x9cC1-C6alkylxe2x80x9d or xe2x80x9calkylxe2x80x9d refers to a straight or branched alkyl group having from 1 to 6 carbon atoms and as referred to herein are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl. The term xe2x80x9cC1-C6alkoxyxe2x80x9d refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms and as referred to herein are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy. The term xe2x80x9cHalxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to a halogen group and includes Cl, Br or I.
The piperidine derivatives of the formula (IX) can form pharmaceutically acceptable salts. Pharmaceutically acceptable acid addition salts of the compounds of this invention are those of any suitable inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric, and phosphoric acids. Suitable organic acids include carboxylic acids, such as, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranillic, cinnamic, salicyclic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids, such as, methanesulfonic, ethanesulfonic and B-hydroxyethanesulfonic acid. Non-toxic salts of the compounds of the above-identified formula formed with inorganic or organic bases are also included within the scope of this invention and include, for example, those of alkali metals, such as, sodium, potassium and lithium, alkaline earth metals, for example, calcium and magnesium, light metals of group IIIA, for example, aluminum, organic amines, such as, primary, secondary or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine. The salts are prepared by conventional means as, for example, by treating a piperidine derivative of formula (I) with an appropriate acid or base.
The novel intermediates of formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII) wherein R5 is hydrogen may be prepared as described in Scheme A. In Scheme A, all substituents are as previously defined unless otherwise indicated. 
Scheme A provides various general synthetic procedures for preparing the novel intermediates of formula (II), formula (III) and formula (IV) wherein R5 is hydrogen.
In step a, the appropriate toluene derivative of structure (1) is methylated to give the corresponding ethylbenzene derivative of structure (2).
For example, the appropriate toluene derivative of structure (1) is reacted with a slight molar excess of an appropriate methylating agent, such as iodomethane, chloromethane or bromomethane in the presence of a suitable non-nucleophilic base, such as potassium t-butoxide or sodium hydride. The reaction is typically conducted in a suitable organic solvent, such as diglyme, tert-butyl methyl ether or methylene chloride, for a period of time ranging from 30 minutes to 24 hours and at a temperature range of from xe2x88x9278xc2x0 C. to room temperature. The corresponding ethylbenzene derivative of structure (2) is recovered from the reaction zone by extractive methods as is known in the art and may be purified by distillation.
In step b, the appropriate ethylbenzene derivative of structure (2) is methylated to give the corresponding cumene derivative of structure (3) as described previously in step a, but using at least 2 molar equivalents of methylating agent.
In step c, the appropriate toluene derivative of structure (1) is dimethylated to give the corresponding cumeme derivative of structure (3) as described previously in step a but using at least 2 molar equivalents of methylating agent.
In step d, the appropriate toluene derivative of structure (1) is acylated with an appropriate xcfx89-halo compound of the structure Hal-(CH2)nxe2x80x94C(xe2x95x90O)xe2x80x94B, wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as previously defined to give the corresponding xcfx89-halo tolylketone compound of structure (4).
For example, the appropriate xcfx89-halo tolylketone compound of structure (4) may be prepared by reacting an appropriate toluene derivative of structure (1) with an appropriate xcfx89-halo compound of the structure Hxcex1xe2x80x2-(CH2)nxe2x80x94C(xe2x95x90O)xe2x80x94B, wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as previously defined, which are known in the art or are prepared by procedures well known in the art, under the general conditions of a Friedelxe2x80x94Crafts acylation using a suitable Lewis acid. The reaction is carried out in a solvent, such as carbon disulfide, 1,2-dichloroethane, n-hexane, acetonitrile, 1-nitropropane, nitromethane, diethyl ether and carbon tetrachloride, methylene chloride, tetrachloroethane or nitrobenzene with methylene chloride being the preferred solvent. The reaction time varies from about xc2xd hour to 25 hours, preferably 10 to 16 hours and the reaction temperature varies from about 0xc2x0 C. to 25xc2x0 C. The corresponding xcfx89-halo tolylketone compound of structure (4) is recovered from the reaction none by an aqueous quench followed by extraction as is known in the art. The xcfx89-halo tolylketone compound of structure (4) may be purified by procedures well known in the art, such as crystallization and/or distillation.
Alternatively, the appropriate toluene derivative of structure (1) may be acylated with the xcfx89-halo compound of the structure Hal-(CH2)nxe2x80x94C(xe2x95x90O)xe2x80x94B, wherein B is hydroxy, Hal is Cl, Br or I and n is as previously defined in the presence of a Lewis acid to give the corresponding xcfx89-halo tolylketone compound of structure (4) as described in Arch. Pharm. 306, 807 1973. In general, an appropriate toluene derivative of structure (1) and the xcfx89-halo compound of the structure Hal-(CH2)nxe2x80x94C(xe2x95x90O)xe2x80x94B, wherein B is hydroxy, are melted together at about 50xc2x0 C., then cooled to about 10xc2x0 C. after which a Lewis acid is added in an amount about 2.2 times the molar amount of the appropriate toluene derivative of structure (1) employed. The mixture is heated at about 70xc2x0 C. for about 2 hours after which a 30% sodium acetate solution is added and extracted with ether. The organic layer is dried and the solvent evaporated to give the corresponding xcfx89-halo tolylketone compound of structure (4). The xcfx89-halo tolylketone compound of structure (4) may be purified by procedures well known in the art, such as crystallization and/or distillation.
Suitable Lewis acids for the acylation reaction described in step d are well known and appreciated in the art. Examples of suitable Lewis acids are boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride, ferric chloride, cobalt(II) chloride and zinc chloride, with aluminum chloride being preferred. The selection and utilization of suitable Lewis acids for the acylation reaction of step d is well known and appreciated by one of ordinary skill in the art.
The starting xcfx89-halo compound of the structure Hal-(CH2)nxe2x80x94C(xe2x95x90O)xe2x80x94B, wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as previously defined are commercially available of easily prepared by generally known methods.
While also not necessary for utilization in the acylation reaction of step d, the phenol functionality of those toluene derivatives of structure (1), wherein A is hydroxy may be protected with a suitable protecting group. For example, suitable protecting groups for the phenolic hydroxy include methyl ether, 2-methoxyethoxymethyl ether (MEM), cyclohexyl ether, o-nitrobenzyl ether, 9-anthryl ether, t-butyldimethylsilyl ether, acetate, benzoate, methyl carbamate, benzyl carbamate, aryl pivaloate and aryl methanesulfonate.
In step e, to appropriate toluene derivative of structure (I) is acylated with an appropriate cyclopropyl compound of the structure 
wherein B is as previously defined to give the corresponding cyclopropyl tolylketone derivative of structure (5) as described previously in step d.
In step f, the appropriate ethylbenzene derivative of structure (2) is acylated with an appropriate xcfx89-halo compound of the structure Hal-(CH2)nxe2x80x94C(xe2x95x90O)xe2x80x94B, wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as previously defined to give the corresponding xcfx89-halo ethylphenylketone compound of structure (6) as described previously in step d.
In step g, the appropriate ethylbenzene derivative of structure (2) is acylated with an appropriate cyclopropyl compound of the structure 
wherein B is as previously defined to give the corresponding cyclopropyl ethylphenylketone derivative of structure (7) as described previously in step e.
In step h, the appropriate cumene derivative of structure (3) is acylated with an appropriate xcfx89-halo compound of the structure Hal-(CH2)nxe2x80x94C(xe2x95x90O)xe2x80x94B, wherein B is Hal or hydroxy, Hal is Cl, Br or I and n is as previously defined to give the corresponding xcfx89-halo cumylketone compound of structure (8) as described previously in step d.
In step i, to appropriate cumene derivative of structure (3) is acylated with an appropriate cyclopropyl compound of the structure 
wherein B is as previously defined to give the corresponding cyclopropyl cumylketone derivative of structure (9) as described previously in step e.
In step j, the cyclopropyl functionality of the appropriate cyclopropyl tolylketone derivative of structure (5) is ring-opened to give the corresponding xcfx89-halo tolylketone compound of structure (4) wherein n=3.
For example, the appropriate cyclopropyl tolylketone derivative of structure (5) is reacted with an appropriate hydrogen halide in a suitable organic solvent, such as toluene, xylene and ethanol. The reaction is typically conducted at a temperature range of from room temperature to 70xc2x0 C. and for a period of time ranging from 20 minutes to 10 hours. The corresponding xcfx89-halo tolylketone compound of structure (4) wherein n=3 is isolated from the reaction zone by evaporation of the solvent or may be stored in a solution of the hydrogen halide.
In step k, the appropriate xcfx89-halo tolylketone compound of structure (4) wherein n =3 is ring-closed to give the corresponding cyclopropyl tolylketone derivative of structure (5).
For example, the appropriate xcfx89-halo tolylketone compound of structure (4) wherein n=3 is reacted with an appropriate non-nucleophilic base, such as sodium hydroxide or potassium hydroxide in a suitable organic protic solvent, such as methanol or ethanol. The reaction is typically conducted at a temperature range of from xe2x88x9210xc2x0 C. to room temperature and for a period of time ranging from 10 minutes to 5 hours. The corresponding cyclopropyl tolylketone derivative of structure (5) is isolated from the reaction zone by extractive methods as are known in the art and may be purified by distillation.
In step 1, the cyclopropyl functionality of the appropriate cyclopropyl ethylphenylketone derivative of structure (7) is ring-opened to give the corresponding xcfx89-halo ethylphenylketone compound of structure (6) wherein n=3 as described-previously in step j.
In step m, the appropriate xcfx89-halo ethylphenylketone compound of structure (6) wherein n=3 is ring-closed to give the corresponding cyclopropyl ethylphenylketone derivative of structure (7) as described previously in step k.
In step n, the cyclopropyl functionality of the appropriate cyclopropyl cumylketone derivative of structure (9) is ring-opened to give the corresponding xcfx89-halo cumylketone compound of structure (8) wherein n=3 as described previously in step j.
In step o, the appropriate xcfx89-halo cumylketone compound of structure (8) wherein n=3 is ring-closed to give the corresponding cyclopropyl cumylketone derivative of structure (9) as described previously in step k.
In step p, the appropriate xcfx89-halo ethylphenylketone compound of structure (6) is methylated to give the corresponding xcfx89-halo cumylketone compound of structure (8) as described previously in step a.
In step q, the appropriate cyclopropyl tolylketone derivative of structure (5) is dimethylated to give the corresponding cyclopropyl cumylketone derivative of structure (9) as described previously in step c.
In step r, the appropriate xcfx89-halo tolylketone compound of structure (4) is methylated to give the corresponding xcfx89-halo ethylphenylketone compound of structure (6) as described previously in step a.
In step s, the appropriate xcfx89-halo tolylketone compound of structure (4) is dimethylated to give the corresponding xcfx89-halo cumylketone compound of structure (8) as described previously in step c.
In step t, the appropriate cyclopropyl ethylphenylketone derivative of structure (7) is methylated to give the corresponding cyclopropyl cumylketone derivative of structure (9) as described previously in step a.
In step u, the appropriate cyclopropyl tolylketone derivative of structure (5) is methylated to give the corresponding cyclopropyl ethylphenylketone derivative of structure (7) as described previously in step a.
Starting materials for use in Scheme A are readily available to one of ordinary skill in the art.
The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: xe2x80x9cgxe2x80x9d refers to grams; xe2x80x9cmmolxe2x80x9d refers to millimoles; xe2x80x9cmLxe2x80x9d refers to milliliters; xe2x80x9cbpxe2x80x9d refers to boiling point; xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cmm Hgxe2x80x9d refers to millimeters of mercury; xe2x80x9cxcexcLxe2x80x9d refers to microliters; xe2x80x9cxcexcgxe2x80x9d refers to micrograms; and xe2x80x9cxcexcMxe2x80x9d refers to micromolar.